Frontotemporal lobar degeneration (FTLD), a common cause of early-onset dementia, encompasses a group of disorders with significant genetic, clinical and neuropathological heterogeneity. Understanding the diverse underlying mechanisms of FTLD pathogenesis is a fundamental area of interest of my research program. To accelerate scientific discovery, we have adopted a comprehensive approach that investigates multiple FTLD mechanisms driven by key molecular players (e.g., TDP-43, progranulin, and tau). We also place great emphasis on translational research geared towards identifying much needed biomarkers and therapies, an area of particular importance given that there exists no treatment for FTLD. Our endeavors to uncover the pathomechanisms associated with TDP-43, tau and FTLD-causing mutations have yielded seminal findings published in high-impact journals. For instance, in the five years since the discovery of the G4C2 repeat expansions in C9ORF72 as the most common known cause of FTLD, my group identified a new neuropathological hallmark specific to this mutation, namely the accumulation of proteins of repeating dipeptides synthesized from the expansion; made significant strides in elucidating mechanisms of disease relating to these so-called c9RAN proteins; identified promising therapeutic strategies and potential biomarkers for C9ORF72 repeat expansion carriers; and developed the first mouse model to recapitulate both neuropathological and clinical features of patients. Our productivity is influenced by the excellent research environment fostered at Mayo Clinic, which brings together highly interactive and devoted neurobiologists, geneticists, neuropathologists and physician scientists, as well as the numerous collaborations we have forged with world-renowned experts in the field. Herein, we propose to extend our discoveries by addressing impactful questions, some of which may be high risk, but all with clear potential to be transformative to the field. Of importance, the nature of the R35 mechanism will allow us the flexibility to explore intriguing new directions that emerge from our findings and those of others, ensuring that our studies remain timely and relevant. Overall, with the goal of advancing our understanding and developing therapies for FTLD, we propose mechanistic and translational investigations relating to three main areas: 1) C9ORF72-linked FTLD-TDP; 2) GRN-linked FTLD-TDP; and 3) FTLD-Tau. We will explore various therapeutic approaches, seek to identify disease-relevant biomarkers in cerebrospinal fluid and blood, and develop and improve FTLD animal models.